The development of a safe and effective HIV vaccine is reliant on our ability to identify and understand correlates of HIV-1 immunity and protection. The identification of such correlates has been hampered by relatively rare instances of natural immunity that have withstood the challenge of viral exposure. Over the past 13 years, we have established an international collaborative research effort to study the biology of HIV-2 infection and its interaction with HIV-1 in Senegal, West Africa. Not only is HIV-2 infection less readily transmitted by heterosexual and perinatal routes, but progression to AIDS is substantially slower compared to HIV-1. Thus, we hypothesized that a related yet attenuated virus infection might provide protection from the more virulent HIV-1 virus. In 1995, we described studies of HIV-2 infected women that demonstrated such protection and, to date, >60% protection continues in this cohort with 13+ years of observation. The mechanisms for the postulated protective effect in HIV-2 infection remains unclear, although host cellular immune responses may play an important role. Comprehensive studies of the immune responses elicited in HIV-2 infection are still lacking and could support the protective role of cellular immune response against HIV-1 infection. In addition, the evaluation of CTL and T helper responses in HIV-2 infection will offer crucial information in understanding the immunopathogenesis of HIV. We will take advantage of our unique cohort population of women at high risk for both HIV-1 and HIV-2 in order to identify those women that have been superinfected and those HIV-2 infected women that possess determinants suggestive of HIV-1 exposure, i.e., the protected individuals. Comparison of the cellular immune responses in these two groups of women will include: (a) evaluating the spectrum of CTL responses in HIV-2 infection and determining the level of cross-reactivity with HIV-1; (b) fine mapping of the immunogenic HIV-2 CTL epitopes; (c) assessing these CTLs in a functional inhibition assay and (d) studying the HIV-2 T helper function and determining if these proliferative responses are cross-reactive with HIV-1. Not only will these studies provide new information on the breadth and cross-reactivity of the HIV-2 cellular immune responses, but we also hope to correlate such responses with HIV-1 protection in vivo.